Genomics

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Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling: ChIPSeq


ABSTRACT: CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.

ORGANISM(S): Mus musculus  

SUBMITTER: Hong-Wei Sun  Arian Laurence   Kamran Ghoreschi   John Grainger   Xiang-Ping Yang   Wanjun Chen   Nicolas Bouladoux   Joanne Konkel   John J O'Shea   Mandy J McGeachy   Yasmine Belkaid   Todd Davidson   Wendy T Watford   Daniel J Cua   Cristina M Tato   Haydeé L Ramos   Lai Wei   Yuka Kanno   Ethan Shevach   Gérard Eberl   Qian Chen    

PROVIDER: E-GEOD-23681 | ArrayExpress | 2010-08-31

SECONDARY ACCESSION(S): SRP003810GSE23681PRJNA130797

REPOSITORIES: GEO, ArrayExpress, ENA

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CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficient  ...[more]

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